Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway

Kim, Gyeongmi; Jang, Se-Kyeong; Kim, Yu Jin; Jin, Hyeon‐Ok; Bae, Seunghee; Hong, Jungil; Park, In-Chul; Lee, Jae Ho

doi:10.3390/ijms23158761

Cited by 17 publications

(8 citation statements)

References 80 publications

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“…Chemotherapy resistance remains a critical factor in therapeutic failures among patients with EOC. Amino acid metabolism reprogramming sustains stem cell-like characteristics and drug resistance in EOC cells [ 40 , 41 ]. Notably, our findings indicate that CBR-5884 reduced tumorsphere formation ability and CD44 expression levels, suggesting a decrease in the stemness of OC cells.…”

Section: Discussionmentioning

confidence: 99%

Preclinical efficacy of CBR-5884 against epithelial ovarian cancer cells by targeting the serine synthesis pathway

Gong,

Huang,

Zheng

et al. 2024

Discov Onc

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Reprogramming of the serine synthesis pathway (SSP) is intricately linked to the progression of epithelial ovarian cancer (EOC). CBR-5884, a selective small-molecule inhibitor targeting phosphoglycerate dehydrogenase (PHGDH), effectively impedes the de novo synthesis of serine within cancer cells. This study aimed to evaluate the inhibitory effect of CBR-5884 on EOC cells and delineate its specific mechanism, thereby proposing a novel therapeutic approach for treating EOC. The suppression of serine biosynthesis after CBR-5884 treatment was evaluated using RNA sequencing and a serine assay kit, and the results showed that CBR-5884 effectively downregulated serine biosynthesis in EOC cells, particularly those expressing high levels of PHGDH. In vitro studies revealed that CBR-5884 demonstrated significant antitumor effects and suppressed migration and invasion of EOC cells through down-regulation of the integrin subunit beta 4 (ITGB4)/extracellular signal-regulated kinase (ERK)/epithelial–mesenchymal transition signal axis. Additionally, CBR-5884 mitigated the stemness of EOC cells and heightened their sensitivity to chemotherapy. Moreover, in vivo studies revealed that CBR-5884 significantly delayed tumor growth, with histological analysis indicating the safety profile of CBR-5884. Finally, the patient-derived organoid (PDO) models were utilized to explore the preclinical efficacy of CBR-5884 against EOC cells, and the results unveiled that CBR-5884 impeded proliferation and downregulated the expression of ITGB4 in EOC PDO models. Our findings supports the anticancer properties of CBR-5884 in EOC cells exhibiting high PHGDH expression, manifesting through the suppression of proliferation, migration, and invasion, while enhancing chemotherapy sensitivity, suggesting that CBR-5884 holds promise as an efficacious strategy for the treatment of EOC.

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Section: Discussionmentioning

confidence: 99%

Preclinical efficacy of CBR-5884 against epithelial ovarian cancer cells by targeting the serine synthesis pathway

Gong,

Huang,

Zheng

et al. 2024

Discov Onc

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“…Simultaneous blocking of glutaminase by CB-839, and of Gln import with V-9302, has shown synergistic effects in hepatocellular carcinomas [ 15 ]. The same ASCT2 transporter inhibitor has also been successfully used to resensitise Paclitaxel-resistant ovarian cancer cells [ 46 ]. Targeting glutaminase with CB-839 has also shown synergy with Bruton tyrosine kinase inhibition in ibrutinib-resistant mantle B-cell lymphoma cells [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells

Sbirkov

Vergov

Dzharov

et al. 2023

IJMS

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The prognosis for patients with relapsed childhood acute lymphoblastic leukaemia (cALL) remains poor. The main reason for treatment failure is drug resistance, most commonly to glucocorticoids (GCs). The molecular differences between prednisolone-sensitive and -resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to elucidate at least some aspects of the molecular differences between matched pairs of GC-sensitive and -resistant cell lines. To address this, we carried out an integrated transcriptomic and metabolomic analysis, which revealed that lack of response to prednisolone may be underpinned by alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signalling, which are also known to control cell metabolism. In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-α-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. Among other druggable targets that were identified in this study, inhibition of glutamine metabolism presents a potential therapeutic approach in GC-sensitive, but more importantly, in GC-resistant cALL cells. Lastly, these findings may be clinically relevant in the context of relapse—in publicly available datasets, we found gene expression patterns suggesting that in vivo drug resistance is characterised by similar metabolic dysregulation to what we found in our in vitro model.

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“…Thus, we confirmed the upregulation of serine and glycine metabolism affecting paclitaxel resistance in ES2 cells compared to parental cells. A recent study revealed that arginine and glutamine conditions could target amino acid metabolism to suppress survival in ovarian cancer, independent of paclitaxel resistance [42]. Although glutamine deprivation-induced cytotoxicity was reported, little is known about the effects of the serine-glycine metabolic pathway on paclitaxel resistance in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel resistance of ovarian clear cell carcinoma reveals the ABC- and SLC- transporter genes to mediate glycolytic metabolism.

Lin,

Li,

Lin

et al. 2023

Preprint

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Background Ovarian clear cell carcinoma (OCCC) often becomes resistant to platinum based therapy when at an advanced stage. However, metabolic phenotypes and changes in its resistance remain unclear. Hence, we investigated the metabolic effect of paclitaxel resistance in OCCC and normal ovarian epithelium OSE2a cells. Methods The viability and cytotoxicity of paclitaxel resistant cells were determined. Glycolytic stress was measured using a Seahorse extracellular flux analyzer. RNA sequencing (RNA-Seq) was used to elucidate differentially expressed genes upon paclitaxel resistance Comprehensive metabolomics (capillary electrophoresis time of flight mass spectrometry (CE-TOFMS and CE-QqQMS) and transcriptomics analysis (RNA-Seq) were performed to characterize metabolic pathways in paclitaxel resistant OCCC cells. Results ES2 resistant cells had slower ATP and guanosine 5' triphosphate (GTP inflow and a greater nicotinamide adenine dinucleotide (NADH/NADH coenzyme (NAD ratio with an elevated oxygen consumption rate. Sets of ABC binding cassette (ABC- and solute carrier (SLC) transporter genes were found to be enriched in ES2 resistant cells involving glycolysis metabolism and molecular transport. We further demonstrate d that in response to high paclitaxel resistance, characteristic metabolomic changes in ES2 cells were a reduction in the energy requiring phase of glycolysis and the induction of metabolites in the energy releasing phase of glycolysis . Moreover, metabolite levels of selected cancer related nonessential amino acids, including serine glycine metabolism increased with paclitaxel resistance. Conclusions This is the first work to elucidate metabolic profiles of paclitaxel resistance in OCCC cells, indicating possible underlying mechanisms by which cells respond to paclitaxel cells, indicating possible underlying mechanisms by which cells respond to paclitaxel therapy through therapy through ABC-- and SLC--transporter genes, thereby affecting glycolysis transporter genes, thereby affecting glycolysis metabolism metabolism inin response to paclitaxel resistance.response to paclitaxel resistance.

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Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway

Cited by 17 publications

References 80 publications

Preclinical efficacy of CBR-5884 against epithelial ovarian cancer cells by targeting the serine synthesis pathway

Preclinical efficacy of CBR-5884 against epithelial ovarian cancer cells by targeting the serine synthesis pathway

Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells

Paclitaxel resistance of ovarian clear cell carcinoma reveals the ABC- and SLC- transporter genes to mediate glycolytic metabolism.

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